Nrf2 Suppresses Allergic Lung Inflammation by Attenuating the Type 2 Innate Lymphoid Cell Response

Nagashima, Ryuichi; Kosai, Hitomi; Masuo, Masahiro; Izumiyama, Keiko; Noshikawaji, Taketo; Morimoto, Motoko; Kumaki, Satoru; Miyazaki, Yasunari; Motohashi, Hozumi; Yamamoto, Masayuki; Tanaka, Nobuyuki

doi:10.4049/jimmunol.1801180

Cited by 27 publications

(19 citation statements)

References 34 publications

(51 reference statements)

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“…IL-33 contributes significantly to sepsis-induced inflammation in the lung, early inflammation-associated lung injury, and systemic inflammatory response in the early phase of sepsis by upregulating the level of ILC2s [ 33 ]. A recent study demonstrated that attenuating the ILC2s response activated by IL-33 suppresses the allergic lung inflammation [ 34 ]. However, whether the expansion of ILC2s is responsible for IL-33-mediated damage in BPD has not been addressed before.…”

Section: Discussionmentioning

confidence: 99%

Tissue-Resident Type 2 Innate Lymphoid Cells Arrest Alveolarization in Bronchopulmonary Dysplasia

Zhu

Cai

et al. 2020

Journal of Immunology Research

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Bronchopulmonary dysplasia (BPD) is a severe complication of the respiratory system associated with preterm birth. Type 2 innate lymphoid cells (ILC2s) play a major role in tissue homeostasis, inflammation, and wound healing. However, the role in BPD remains unclear. The present study showed that ILC2s, interleukin-4 (IL-4), IL-13, and anti-inflammatory (M2) macrophages increased significantly in BPD mice as compared to the control mice. Administration with recombinant mouse IL-33 amplified the above phenomena and aggravated the alveolar structural disorder and functional injury in mice subjected to BPD, and the opposite was true with anti-ST2 antibody. In addition, the depletion of ILC2s in BPD mice with anti-CD90.2 antibody substantially abolished the destructive effect on BPD. In the treatment of BPD with dexamethasone, the number of ILC2s and M2 macrophages and levels of IL-4 and IL-13 decreased with remission as compared to the control group. This study identified a major destructive role of the ILC2s in BPD that could be attenuated as a therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

Tissue-Resident Type 2 Innate Lymphoid Cells Arrest Alveolarization in Bronchopulmonary Dysplasia

Zhu

Cai

et al. 2020

Journal of Immunology Research

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“…Oxidative stress is known to increase in patients with asthma 20) and is suggested to prompt a reduction in corticosteroid responsiveness. 21) Nrf2 generally plays a crucial role in antioxidant mechanisms, 7,8) but it was recently shown to have various effects on the pathogenesis of asthma; activating Nrf2 enhances the stabilization of the airway epithelial barrier 22) and suppresses the allergic lung inflammation induced by type 2 innate lymphoid cells, 23) which play a pivotal role in the development of steroid resistance. 24) Taken together, the data suggest that Nrf2 dysfunction might reflect the progression of airway inflammation.…”

Section: Discussionmentioning

confidence: 99%

Impact of Gene Expression Associated with Glucocorticoid-Induced Transcript 1 (GLCCI1) on Severe Asthma and Future Exacerbation

Hirai

Shirai

Rachi

et al. 2019

Biological & Pharmaceutical Bulletin

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Genetic variations in glucocorticoid-induced transcript 1 (GLCCI1) have been associated with the response to corticosteroid treatment. However, the associations of GLCCI1 polymorphisms or gene expression with the prognosis of asthma and pathophysiological factors related to steroid insensitivity remain unclear. We sought to investigate the associations of GLCCI1, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and histone deacetylase 2 (HDAC2) mRNA expression levels and the GLCCI1 rs37973 polymorphism with asthma severity and future exacerbation in patients with asthma. Subjects included 25 patients with severe asthma and 127 patients with nonsevere asthma. mRNA expression levels in peripheral blood mononuclear cells were measured and evaluated as predictors of severe asthma using receiver operating characteristic (ROC) analysis. The hazard ratios of the mRNA expression levels for time to first exacerbation in the 1-year follow-up period were calculated. GLCCI1, Nrf2, and HDAC2 mRNA expression levels were significantly lower in patients with severe asthma than in patients with nonsevere asthma and could predict severe asthma with an area under the ROC curve of 0.68, 0.71, and 0.65, respectively. In contrast, no relationship was found between the GLCCI1 rs37973 polymorphism and severe asthma. The hazard ratios for asthma exacerbation in patients with low GLCCI1, Nrf2, and HDAC2 mRNA expression levels were 3.24 (95% confidence interval, 1.42-7.40), 3.13 (1.37-7.16), and 2.98 (1.22-7.25), respectively. Patients with severe asthma could be distinguished by lower GLCCI1, Nrf2, and HDAC2 mRNA levels in peripheral blood cells, and all of these gene signatures could predict future asthma exacerbations.

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“…Knockout of nrf2 delayed proliferation of hepatocytes after hepatectomy (31). Nevertheless, type 2 innate lymphoid cells from nrf2-de cient mice underwent hyperproliferation in response to the stimulation of IL-33 combined with IL-2, IL-7, or thymic stromal lymphoprotein (32). ML385 is a probe molecule that binds to the Neh1 domain of nrf2 and interferes the binding of V-maf avian musculoaponeurotic brosarcoma oncogene homologue G with nrf2 and blocks the nrf2 targeted genes expression (33).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of nrf2 exacerbates TNF-α-induced proliferation and invasion of rheumatoid arthritis fibroblast-like synoviocytes through activating JNK pathway

Wang

Tian

et al. 2020

Preprint

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Background. Fibroblast-like synoviocytes (FLS) in the synovial tissue of rheumatoid arthritis (RA) exhibit over-proliferative and aggressive phenotypes, which participate in the pathophysiology of RA. In RA, little is known about the non-antioxidant effect of nuclear factor erythroid 2-related factor 2 (nrf2), master regulator of redox homeostasis. In this study, we explored the expression and upstream regulatory factors of nrf2, and revealed its functions in modulating the proliferation and invasion in RA-FLS. Methods. FLS were isolated from RA and osteoarthritis patients. Expression of nrf2 in the synovial tissues and FLS was analyzed by immunohistochemistry, real-time PCR, western blot, and immunofluorescence. Cell proliferation was examined by Cell Counting Kit-8, and cell invasion was tested by transwell assay. Phosphorylation of JNK was determined by Western blot. Results. Nrf2 expression in the RA synovial tissues was upregulated. TNF-α promoted expression and nuclear translocation of nrf2 in RA-FLS, and increased the intracellular reactive oxygen species (ROS) level. Nrf2 nuclear translocation was blocked by ROS inhibitor N-acetylcysteine. Both knockdown of nrf2 by siRNA and inhibition of nrf2 by ML385 significantly promoted the TNF-α-induced proliferation and invasion of RA-FLS. Activation of nrf2 by sulforaphane (SFN) profoundly inhibited the TNF-α-induced proliferation and invasion of RA-FLS. Knockdown of nrf2 also enhanced the TNF-α-induced matrix metalloproteinases (MMPs) expression and phosphorylation of JNK in RA-FLS. Proliferation and invasion of RA-FLS incubated with TNF-α and nrf2 siRNA was inhibited by pre-treatment with JNK inhibitor SP600125. Conclusion. Taken together, nrf2 is over-expressed in synovial tissues of RA patients, which may be induced by TNF-α and ROS levels. Increased nrf2 may suppress TNF-α-induced proliferation, invasion, and MMPs expression in RA-FLS through inhibiting JNK activation, indicating that nrf2 plays a protective role to relieve the severity of synovitis in RA.

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Nrf2 Suppresses Allergic Lung Inflammation by Attenuating the Type 2 Innate Lymphoid Cell Response

Cited by 27 publications

References 34 publications

Tissue-Resident Type 2 Innate Lymphoid Cells Arrest Alveolarization in Bronchopulmonary Dysplasia

Tissue-Resident Type 2 Innate Lymphoid Cells Arrest Alveolarization in Bronchopulmonary Dysplasia

Impact of Gene Expression Associated with Glucocorticoid-Induced Transcript 1 (GLCCI1) on Severe Asthma and Future Exacerbation

Knockdown of nrf2 exacerbates TNF-α-induced proliferation and invasion of rheumatoid arthritis fibroblast-like synoviocytes through activating JNK pathway

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